Nuclear receptors are a large class of proteins that are responsible for the regulation of complex cellular events including cell differentiation, homeostasis, the growth and functioning of various organs and tissues, and transcription. It is believed that nuclear receptors function by transducing extracellular chemical signals from hormones into a transcriptional response.
Estrogen receptors are a subclass of the larger nuclear receptor class. The estrogen receptors are proteins that are responsive to estrogen and estrogen-like molecules. Estrogen receptors are believed to play an important role in the mammalian endocrine system, the reproductive organs, breast tissue, bone tissue, and the vascular system, and are believed to be involved in the development and progression of various disease states such as abnormal bone resorption, cardiovascular disease, cancer, and central nervous system disorders. It is believed that various disease states and conditions can be treated or prevented by the development of appropriate ligands, i.e. drugs, for modifying the activity of estrogen receptors. Consequently there is a need to identify estrogen receptors and their mode of action and to also identify ligands for modifying the action of these receptors.
At least two distinct types of estrogen receptors have been reported. An estrogen receptor having 595 amino acids is disclosed in Green, S. et al., Nature, 320, pp. 134-139 (1986) and Greene, G. L. et al., Science, 231, pp. 1150-1154 (1986), both of which are incorporated by reference herein in their entirety. These references also disclose the corresponding DNA sequences for the receptor.
The other reported type of estrogen receptor has been disclosed by two research groups and has been designated ".beta." (beta). One research group discloses a 485 amino acid .beta. receptor that is obtained from rat, human, and mouse sources, as well as the corresponding DNA sequences. See PCT application No. WO 97/09348, to Kuiper, G. G. J. M. et al., published Mar. 13, 1997, which is incorporated by reference herein in its entirety. The second research group discloses a similar estrogen receptor containing 483 amino acids. The corresponding DNA sequence is also disclosed. See Mosselman, S. et al., ER.beta.: identification and characterization of a novel human estrogen receptor, FEBS Letters, 392, pp. 49-53 (1996), which is incorporated by reference herein in its entirety.
In the present invention, a novel estrogen receptor having 548 amino acid units, and that is distinct from the disclosed 595 amino acid, 485 amino acid, and 483 amino acid estrogen receptors, has been identified and isolated from human tissue. It is believed that this novel estrogen receptor plays a key role in mammalian physiology. This novel estrogen receptor is an important research tool for identifying and designing ligands for use in pharmaceutical compositions for treating and/or preventing a wide range of estrogen receptor mediated diseases or conditions.
It is therefore an object of the present invention to provide a novel isolated estrogen receptor.
It is another object of the present invention to provide the amino acid sequence of a novel estrogen receptor.
It is another object of the present invention to provide the polynucleotide sequence encoding a novel estrogen receptor.
It is another object of the present invention to provide methods for isolating a novel estrogen receptor.
It is another object of the present invention to provide ligands capable of binding to a novel estrogen receptor.
It is another object of the present invention to provide pharmaceutical compositions comprising ligands capable of binding to a novel estrogen receptor.
It is another object of the present invention to provide methods for treating and/or preventing estrogen receptor mediated diseases or conditions.
These and other objects will become readily apparent from the detailed description which follows.